Brain-resident macrophages regulate CSF flow dynamics and meningeal lymphatic development

Macrophages are known to be highly adapted to their tissue of residence where they perform specialized functions and maintain tissue homeostasis. Within the central nervous system, distinct subsets of tissue-resident macrophages have been identified. Microglia are the tissue-resident macrophages present within the brain parenchyma, whereas other macrophage subsets, collectively known as border-associated macrophages (BAMs), are found in the dura mater, the leptomeninges, the perivascular spaces and the choroid plexus. Recent findings have highlighted the phenotypic heterogeneity among these populations. However, their functional heterogeneity and the signals that are required for these subsets to adopt their respective profiles remain elusive. In our study, we demonstrate that the transcription factor c-Maf is a master regulator of brain macrophage identity and function. Through genetic manipulation and single-cell technologies, we show that c-Maf deletion in macrophages changes all Lyve1-high BAMs into MHCII-high BAMs and pushes microglia into a more reactive state. Upon c-Maf knock-out, mice also display changes in brain morphology and cerebrospinal fluid (CSF) flow dynamics leading to an increased incidence of hydrocephaly. Additionally, our results also highlight the involvement of BAMs in the development of the meningeal lymphatics. Our findings offer new insights into the multifaceted role played by macrophages within the brain during homeostatic and inflammatory conditions. Ultimately, this renewed understanding of brain macrophages sheds light on potential treatments for neurological disorders.